Arthritis or arthralgia generally refers to inflammatory disorders of the joints of the body, and is usually accompanied by pain, swelling and stiffness. Arthritis may result from any of several causes including infection, trauma, degenerative disorders, metabolic disorders or disturbances or other unknown etiologies. Arthritis may be more specifically described as, for example, rheumatoid arthritis, osteoarthritis, bacterial or infectious arthritis. Arthritis may further accompany other identified disorders, including gout, ankylosing spondylitis, inflammatory bowel disease or psoriasis.
In normal joints, a small amount of synovial fluid (SF) lubricates cartilage and the synovium, and acts as a reservoir for solutes and a few resting mononuclear and synovial cells (3). During chronic inflammation, SF volume and the concentration of immune cells and soluble proteins increase (4).
For some forms of arthritis, such as rheumatoid arthritis (RA), the specific cause may not be known. RA is regarded as a “multifactorial threshold model”, in which many genetic and environmental influences must act on the same person in order for the disease to manifest (1). As a specific target is lacking, current therapies are primarily aimed at suppression of the inflammatory response (2). A hallmark of RA is synovial hyperplasia, characterized by fibroblast-like synoviocyte (FLS) proliferation and inflammatory cell infiltration into the subintima, or outer layer of the synovium (5). The FLS, which comprise about two-thirds of the synovium population, have a well-defined secretory system (5) and secrete large amounts of destructive matrix metalloproteases (MMPs) in RA (6), specifically MMP-1, 3, 8, 9, 10, 11 and 13 (7-11). Numerous researchers have shown that MMP-1 and MMP-3 play important roles in RA (12) and that the collagenase (MMP-1) is the most abundant (6). Both MMP-1 and MMP-3 are biomarkers that have been shown to have predictive validity for structural damage in RA. Local expression of MMPs in arthritis, especially MMP-1, is particularly prominent in the joint pannus adjacent to the site of cartilage and bone destruction (13). The collagenases, particularly MMP-1, cleave native collagen molecules at neutral pH, rendering the collagen susceptible to further enzymatic degradation (14).
Known factors that activate FLS to produce MMP-1 include pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF-alpha), and both are involved in RA (15). IL-1alpha and TNF-alpha are capable of stimulating the production of other MMPs and stromelysins in synovial fibroblasts and chondrocytes in vitro (16). The interactions of FLS with TNF-alpha or IL-1 alpha from activated T cells induces expression of MMP-1 (17). T-cells can also activate FLS to produce an array of inflammatory mediators (18). This cyclical feedback loop between FLS and T cells and their respective cytokines lead to activation and proliferation of T cells and favours the persistent inflammation observed in RA (19-21). It has been suggested that therapeutic anti-TNF alpha antibodies neutralize TNF alpha and block the T cell activation that leads to this persistent state (22).
14-3-3 proteins are a family of dimeric proteins involved in a range of functions (23-24). There are seven mammalian 14-3-3 isoforms: beta (β), gamma (γ), epsilon (ε), eta (η), sigma (σ), tau (τ) and zeta (ζ). Since the discovery of the first 14-3-3 protein in 1967 (26), the members of the 14-3-3 protein family have been repeatedly re-discovered based on their new biological activities, primarily in signal transduction pathways. They have been identified as activators of tryptophan and tyrosine hydroxylase (27-28) and PKC inhibitors (29). Subsequent studies identified the 14-3-3 proteins as molecules that interact with PKCs, Raf family members and now more than 200 other intracellular proteins with critical biological functions (30-31) including cellular response to DNA damage and cell cycle regulation (32-34).